Role of thymic stromal lymphopoietin in chronic rhinosinusitis Abstract: The overall goal of the studies in this project is to test the hypothesis hat Th2-related inflammatory responses in polypoid chronic rhinosinusitis are mediated, in part, by expression of the cytokine thymic stromal lymphopoietin (TSLP) in sinus tissue. Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses that is unresponsive to antibiotic therapy and which persists for at least 12 weeks. It is one of the most common chronic diseases in adults in the United States, affecting over 20 million Americans, and has a severe impact on patients' quality of life and healthcare costs. CRS is most commonly treated with antibiotics, steroids, and allergy medications. Due to poor responses to medical therapy, over 250,000 surgical procedures are performed annually in the United States. Therefore it is necessary that we better understand the pathogenic mechanisms of this disease in order to generate novel medical treatments. CRS is clinically classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Both forms are characterized by intense inflammatory cell infiltration which drives symptoms of the disease, but CRSwNP is the more severe form of the two and is characterized by Th2-related inflammation including eosinophilia. However, the regulation of Th2 inflammation in CRSwNP is still largely unknown. In this proposal we will focus on TSLP, a cytokine that is recognized as a master regulator of Th2 inflammation. We have exciting evidence that TSLP is highly up-regulated in nasal polyps from patients with CRSwNP and high levels of TSLP are significantly correlated with eosinophilia and expression of Th2 cytokines in nasal polyps. In addition, we have found that nasal polyp extracts can truncate TSLP, and the truncated products may have more potent activity than the full-length form. We therefore hypothesize that TSLP and its truncated products play an important pathogenic role in CRSwNP. We propose experiments to test this hypothesis using in vitro and in vivo approaches. We are compelled to test this hypothesis in humans because TSLP has species-specific activities and there is no animal model of CRS. Studies in Aim 1 will test the hypothesis that the family of serine proteases plays an important role in the posttranslational modification of TSLP in NPs. Studies in Aim 2 will test the hypothesis that posttranslational modification of TSLP by NP proteases results in higher TSLP activity than the full-length form. Studies in Aim 3 will test the hypothesi that TSLP and truncated TSLP play an important role in Th2-related inflammation in NPs. We believe that the proposed studies will reveal whether TSLP and truncated TSLP are potential targets for medical treatment of CRS.